CLINICAL MODULATION OF OXIDATIVE DNA DAMAGE BY DIET

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Oxidative DNA damage occurs as a result of normal, metabolic events. This type of DNA damage has been suggested to play a role in endogenous carcinogenesis. It therefore may be expected that the levels of oxidative DNA damage can be used as a marker of cancer risk. Breast cancer risk in women has been associated with dietary fat and caloric intake. Mammary gland tumorigenesis in laboratory animals also has been shown to be modulated by dietary fat and calories. Recent studies have indicated the oxidative DNA damage levels can be modulated by diet. The relative importance of dietary fat and calories on breast cancer risk in humans, however, remains unknown. In this proposed study, the impact of dietary fat and calories on the levels of oxidative DNA damage levels in peripheral nucleated blood cells will be examined in women during dietary change. The women will be randomized to remain on one of four diets for 12 weeks: control, low-fat (15% of calories from fat), calorie-restricted (25% restriction), and a combination of low-fat and calorie-restricted. biweekly, individualized dietary counseling will be provided by registered dietitians. Computer analyses of the diet will be performed at monthly intervals using 4-day food records. As markers of oxidative DNA damage, 5 hydroxymethyluracil and 8-hydroxyguanine will be quantified biweekly in DNA from nucleated blood cells by gas chromatography-mass spectrometry. The 2X2 factorial study design will allow for the detection of clinically meaningful differences among groups with high statistical power. The independent and synergistic effects of fat and calories on oxidative DNA damage levels will be evaluated. Use of oxidative DNA damage as an intermediate marker will allow for the rapid assessment of the influence of dietary change on cancer risk reduction.